The complement system is uniquely designed to recognize, destroy and facilitate the removal of pathogens that are constantly trying to invade our bodies. The system is composed of approximately 30 plasma and cell surface proteins that incorporate both humoral and cellular effector mechanisms to provide redundant and highly efficient protection from infection. Analogous to the clotting cascade, the complement system is activated by association of specific proteins to form active complexes, generally with serine protease activity. These protease complexes activate precursor proteins that contribute to further activation (amplifying the response) or generate inflammatory mediators and cytotoxic elements. There are three main effectors generated during complement activation: C3b, C5a and C5b-9 (also called the membrane attack complex or MAC).
Cellular rejection of transplanted organs can be managed by an array of cellular immune-suppressant drugs that specifically target the cellular immune response. However, a significant population of potential transplant candidates present with donor specific antibodies (DSA) that is often a contraindication for proceeding with transplantation. In addition, de novo anti-donor antibody formation appears to occur in 10-20% of transplanted patients that did not present with high panel reactivity before the transplant. These antibodies bind to the donor organ and initiate an inflammatory response by the host that results in compromised function and ultimately graft loss. Antibody-Mediated Rejection (AMR) is not controlled by standard immune-suppressant drugs and is increasingly recognized as a leading cause of organ rejection. DSA are able to activate the complement system, initially through classical pathway mechanisms, augmented by alternative pathway components that damage the donor organ. In addition, complement activation in the transplant setting has been suggested to occur during the surgical process of transplantation (by ischemia-reperfusion mechanisms). Complement activation products have also been demonstrated to prime and accentuate cellular rejection mechanisms. Thus, complement may contribute to the loss of a transplanted organ in a variety of ways. Factor H, which controls the conversion of C3 to C3a as well as the subsequent generation of C5a, may be effective in limiting organ rejection.
The evidence for a role of complement activation in the pathology of RA is fairly extensive. Studies indicate that complement activation contributes to the pathology of RA. Elevated activation markers in RA patients and the significant protection from disease phenotype that is observed in various rodent models where different complement proteins are absent also suggests an important role for complement in RA etiology. However, work from a number of groups have demonstrated that targeting the complement inhibitor appears to be necessary to show efficacy, and that systemic administration of the un-targeted inhibitor, including FH, was ineffective. In addition, the lack of any genetic association of FH polymorphism with the development of RA appears to further weaken the link with this disease. Surprisingly, as demonstrated herein, FH given systemically does limit the pathology of RA in a mouse model.
Thus, Factor H, as a protein component of the alternative pathway of complement encoded by the complement factor G gene, may be a potential therapeutic for use in preventing or inhibiting allograft rejection and for treating rheumatoid arthritis.